Diaminoquinazolines and method of



DIAMINOQUINAZOLINES AND METHOD OF w, i a George Hitchin gs, Yonkers, and Elvira Falco and Kurt W. Ledig, New Rochelle,-'N;Y., assignors to Burro'ughs Wellcome & Co. .(U.S.A.) Inc., Tuckahoe, N.Y.,

acorporation' of New York p'j- Y i f t T No l lravving. FilediDdct152195Selt15191 780320 f i f 9 Clai'mst 01. 260-2564) The; present invention "relates toin ew derivatives of 2,4-diaminoquinazoline. "lt 'lia been found. that ,substitution by alkyl groups in lam a 1 positions ofl-the benzene moiety markedly enhances lthe antibacterial activity of 2,4-diamincquinazoline resulting in compounds with outstanding; properties as inhibitors oftbacteria, The bacterial spectruminhibited includes a; number of pathogenic organisms such as Escherichiacoli, Sa-lmonel lqtyphosil and- Staphylococcus aurezis, but the newasubstances are a particularly noteworthy for their action on such a trouble-1 someo'rganisrn as.Proteusvulgarisahd in some instances on Pseu'dom'onas aeruginosa. Exemplification of these activitiesris shown in the table below whichwsets forth the zones' r inhibition produced :on seeded agar plates by S.a. E.c. St. 3.8. R PM Diameter of Zone-(mm.)

OH; H H 0 25.5 27 285 22 O 0 H H H 0 r 3L5 35.5 33.5- 29.5 0

H OH, H 27 21 26 17 22 Q H 0 H, H 28 28 28 25 25 -.g

- 0.11 H 30 :33 0. 38 28 t0 --,(CE 2)4-- H 0 34 38' 40 32 12 OE g) H 16.5 36 42 40 33 OH; 8-011; 20 26 19 20 a 0 H OH; 7OH; 22 0 0 17 H -H H 0 17 0 0 S.a.=Staph1 loc0ccus aureus. E.c. =Escherichia colt. S.t.=Salmonella i'jphosa. B.s.=Bac1'Zlus subtilis. P.v.=Prote'us vulgam. Ps.a.=Paeu domorzas aeruginosa.

A number of applicationslof these findings will be apnit d Sta e re y se P" P w r .Ylnviyo experiments against Proteusinfection Seven groups of five white mice each weighing .ap'pr'oxi mately 27 g. each were inoculated intraperitoneally with 0.5 ml. of a 1:50 dilution of-a 6 hour culture of Proteus vulgaris CN329. Test drugs were n administered orally in the doses indicated in 'the table below immediately before inoculation, and the mice were observed for '160 hours. The results are tabulated in terms of average survival time for each group. It will be observed that controls treated with water survived an average of only 46 hours, those treated with'sulfadiazine an averagebfi I 68 hours. 2,4-diarnino-S,6-dimethylenequinazoline at 'a dose of 0 25 mg. gave significant protection alone and potentiative effects when administered with sulfadiazine. The fi -ethylquinazoline derivative, while less actiyejwlieri given'*alone, afforded complete protection whenl given with sulfadiazine. 7 W

Protective efiects of quim zzolines against Proteus infectidns Average I Dose Survival,

* 7 hours water. 0.25 ml 46 Su1fadiazine-- 0.25 mg 68 zii-fiamino-5,6-trimethy1ene-quinazo- 105 2 4-Dlamino-5 fi-trimethylene-qutuazoline Sulfadia'zlne. 2, t-Diarnino-5,fi-trimethylene-quinazo- 160 line Snlfadiazine.

. 2,4-Diamino-5-ethylc ulnazoline 71 2,4-Diamino-S-ethylquinazoline Sulfa- 160 dlazlne.

i The compounds of the present invention can be represented by the following itormulaz r methylene.

Thesenew compounds may be made by the chlorina tion and amination of a suitable 2,4-dihydroxyquin azoline as shown below:

parent to those versed in the art. Thus, solutions ofthe above named compounds are potentantibacterials for topical usethe compounds being used as their soluble" salts in concentrations of the order of 0.01 to 1%. The compounds are suitable 'foru'se alone or in combination with antibiotics and/or'other antibacterial agents;

Alternatively theymay be prepared bythe reaction of a suitably substituted anthranilonitrile with dicyandb amide as follows:

" I NH: R,

NH Ri Patented July 19, 1960 The selection of the particular method depends on the reactivities of the individual compounds. However, it has been found that the second method is a general method which can be used for all of the examples given below.

EXAMPLE 1 V 2,4-diamino-6-methylquinazoline A mixture of 13 g. of 6-methyl-2,4-dihydroxyquinazoline, 40 g. of phosphorus pentachloride and 80 mlnof phosphoryl chloride was heated under reflux conditions for 3 hours. The excess phosphoryl chloride was removedunderreduced pressure and the residue poured over cracked ice and made alkaline with ammonium hydroxide. The precipitate was filtered off and heated with 200 ml. of saturated alcoholic ammonia at 150 for 17 hours. The reaction mixture was evaporated to dryness, dissolved in dilute acetic acidand the product reprecipitated by ammonium. hydroxide, then recrystallized from benzene. V

EXAMPLE 2 2,4-diamin-6-ethylquinazoline reaction mixture was evaporated to dryness, dissolved in dilute acetic acid and the product reprecipitated with ammonium hydroxide. The 2,4-diamino-6-ethylquinazoline after recrystallization from water and then benzene had a melting point of 2l4-2l6.

EXAMPLE 3 2,4-diamino-6,8-dimethylquinaz0line A mixture of 18 g. of 2,4-dihydroxy-6,8dimethylquinazoline, 54 ml. of phosphoryl chloride and 8 ml. dimethylaniline was heated for /2 hours under reflux conditions and then worked up as in Example 2. The 2,4-diamino- 6,8-dimethylquinazoline was recrystallized from boiling Water. I

EXAMPLE 4 V 2,4-diamin0-6,7-dimethylquinazoline The chlorination and amination of 2,4-dihydroxy-6,7-

ml. of concentrated hydrochloric acid dissolves the reaction mixture which after boiling for 5 minutes was poured over ice and made alkaline with sodium hydroxide. The precipitate was filtered, washed and recrystallized from water. The melting point of 2,4-diamino-6-ethylquinazoline is 223-424".

EXAMPLE 7 2,4-diamino-5,6-trimethylenequinazoline Twelve grams of 4-bromo-5-acetylaminoindane and 5 grams of cuprous cyanide were refluxed in 13 ml. of pyridine for 5 hours. The reaction mixture was poured into 50 ml. of 7. N ammonium hydroxide and extracted with a mixture of 100 ml. ether and 100 ml. of benzene. The organic layer was washed with three times 35 ml. of diluted ammonium hydroxide followed by two times 35 ml. of 2 N hydrochloric acid and finally with water. After drying over calcium sulfate, the ether-benzene mixture was filtered and evaporated to 75 ml. The product, 4 cyano-S-acetylaminoindane crystallized out andwas colleoted. It melted at 137-138". V

Four and five-tenths grams of 5-acetylamino-4-cyanoindane was dissolved in 100 ml. absolute alcohol condimethylquinazoline was carried out as described in Ex-.

ample 1. The product was finally recrystallized from methanol and gave a melting point of 291.

EXAMPLE 5 2,4-diamino-5-isopropyl-8-methylquinazoline A mixture'of 11.6 g. of 2,4-dihydroxy-5-isopropyl-8- methylquinazoline and 300 ml. of phosphoryl chloride was heated under reflux conditions for 5 hours and the reaction mixture worked up as in Example 3. The 2,4- diamino derivative was recrystallized from hot water.

EXAMPLE 6 2,4-diamino-6-ethylquinaz0line taining 2 grams of sodium methoxide and refluxed overnight. The reaction mixture was poured over ice in the presence of suflicient acetic acid to neutralize the sodium hydroxide. The 4-cyano-5-aminoindane was extracted with ether and precipitated as the hydrochloride from this solution.

Three and four-tenths grams of 5-amino-4-cyanoindane hydrochloride was thoroughly mixed with 2 g. dicyandiv amide and fused at 160-165 for 15 minutes. The reaction mixture was then dissolved in 50 ml. concentrated hydrochloric acid, poured over ice and made alkaline with sodium hydroxide. The precipitate was washed and recrystallized from alcohol. This product then was dissolved in very dilute formic acid'and put through a Dowex-l (formate) column. The eflluent was neutralized and the crystalline 2,4-diamino-5,G-trimethylenequinazoline collected. The melting point was 288.

EXAMPLE 8 2,4-diamino-5-merhylquinazoline EXAMPLE 9 2,4-diamino-G-propylquinazoline Eight grams of 2-amino-5-propylbenzonitrile was prepared through decomposition of the corresponding 5- isatin oxime.

Eight grams of S-propyI-Z-aminobenzonitrile hydro- .chloride was thoroughly mixed with 3.3 grams of dicyandiamide and worked up as in Example 6. The crude 2,4 diamino-6-propylquinazoline was recrystallized from water. It melted at 194-195 EXAMPLE 10 2,4- diamino-6-butylquinazoline Four grams of S-mbutylisatin-B-oxime was decomposed at 235. The resultant 2-amino-5-butylbenzonitrile was dissolved in ether and the hydrochloride precipitated.

One and six-tenths grams of 2-amino-5-butylbenzonitrile HOl was fused with 650 mg. of dicyandiamide at for 10 minutes. The reaction mixture'was dis- I amide and heated at 155 for 5 minutes.

. 5 solved by the addition of 30 m1. of concentrated hydrochloric acid and 20 m1. of alcohol. After being poured over ice, it was made alkaline with sodium hydroxide. The precipitate was recrystallized from,- water. 2,4-diamino-S-butylqtfinazoline melted at 191-192.

EXAMPLE 11 2,4-diamino-5,6-tetramethylenequinazoline EXAMPLE 12 2,4-diamino-5,6,8-trimethylquinazline Three and eight-tenths grams of 4,5,7-trimethylisatindoxime was decomposed at-240. dissolved in ether and the 2-amino-3,5,6-trimethylbenzonitrile precipitated as the hydrochloride.

Eight hundred mg. of 2-amino-3,5,6-trimethylbenzonitrile was fused with 300 mg. of dicyandiamide at 170 for 10 minutes. The reaction mixture was treated as in Example 6 and the crude product recrystallized from water. 2,4 diamino 5,6,8 trimethylquinazoline has a melting point of l98200.

EXAMPLE l3 2,4-diamin0-5-ethylquinaz0linh Four and eight-tenths grams of the B-oxime of 4-ethylisatin was decomposed and the distillate after being dissolved in ether was precipitated as the hydrochloride.

One and eight-tenths grams of 2-amino-6-ethylbenzonitrile was thoroughly mixed with 850 mg. of dicy-andi- I The reaction mixture was dissolved in concentrated hydrochloric acid "and the compound precipitated with sodium hydroxide.

After repeated recrystallization from water, the 2,4-ditalline material.

What we claim is: 1. 2,4-diamino-5-ethylquinazoline. 2. 2,4-diamino-5,6-trimethylenequinazoline.

The distillate was amino-S-ethylquinazoline was obtained as a white crys- 3. A method for preparing a compound of the formula w wherein R and R are selected from the class consisting of lower alkyl and hydrogen and both together represent a divalent radical of the group consisting of the trimethylene and tetramethylene radicals, which consists of the reaction of an anthranilonitrile of the formula NC R2 wherein R and R have the above values, with dicyandiamide followed by recovery of the diaminoquinazoline.

2,4-diamino-5-methylquinazoline.

. 2,4-diamino-G-methylquinazoline. 2,4-diamino-6-ethylquinazoline.

. 2,4-diamino-6-propylquinazoline.

. A compound selected from the class consisting of A. 11TH, R

NEh-k I and B NH:

wherein R is lower alkyl, R is selected from the class consisting of lower alkyl and hydrogen and wherein R and R together constitute a cycloalkyl chain of from three to four carbon atoms and R is a lower alkyl group.

9. 2,4-diamino-6-tetramethylenequinazoline.

' References Cited in the file of this patent UNITED STATES PATENTS 1,817,982 Hentrich et al Aug. 11, 1931 2,211,710 Zerweck et al Aug. 13, 1940 

8. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF 